Breast cancer aromatase inhibitors for

Cuzick J (2005) Aromatase inhibitors for breast cancer prevention. J Clin Oncol 23 1636-1643... 

Johnston SRD, Dowsett M. Aromatase inhibitors for breast cancer lessons from the laboratory. Nat Rev Cancer 2003 3 821 1. 

AROMATASE INHIBITORS FOR BREAST CANCER EXEMESTANE (AROMASIN ), ANASTROZOLE (ARIMIDEX ), AND LETROZOLE (FEMARA )... 

Despite the significant benefit that tamoxifen has bestowed on breast cancer patients, the third-generation aromatase inhibitors are rapidly replacing tamoxifen as the first-Une treatment for breast cancers. In this chapter, focus will be given to three representative small-molecule aromatase inhibitors for breast cancer exemestane (1, Aromasin ), anastrozole (2, Arimidex ), and letrozole (3, Femara ). 

Buzdar AU (2005—2006) Aromatase inhibitors changing the face of endocrine therapy for breast cancer. Breast dis 24 107-117... 

In a prospective study in 77 consecutive women with postmenopausal breast cancer scheduled to start endocrine treatment for breast cancer, using either tamoxifen or an aromatase inhibitor tamoxifen treatment significantly increased endometrial thickness and uterine volume after 3 months (24). In additional, tamoxifen induced endometrial cysts and polyps and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathology. Furthermore, they reduced endometrial thickness and uterine volume in patients who had previously taken tamoxifen. 

HER-2/new in patients with ER-positive cancers showed significantly worse clinical benefit from hormonal therapies. Furthermore, the study showed a trend toward improved outcome with aromatase inhibitors for patients with elevated serum HER-2/ e , Serum levels of HER-2/ne are also useful in monitoring breast cancer patients because the HER-2/ttew levels decrease in response to treatment. Her-ceptin treatment is now administered only to those breast cancer patients who have HER-2/ e amplification. 

Assikis VJ, Buzdar AU. Recent advances in aromatase inhibitor therapy for breast cancer. Semin Oncol 2002 29(3 Suppl 11) 120—128. 

Initial attempts to develop aromatase inhibitors for use in the treatment of oestrogen-dependent breast cancer involved the use of synthetic steroid analogues of the natural substrates androstenedione and testosterone [53]. Such steroidal inhibitors are reviewed in on p. 272. An alternative approach to the design of aromatase inhibitors was suggested by the discovery [54-56]... 

Aromatase inhibitors as new endocrine therapy for breast cancer. Cancer Treat. Res. 39, 51-65. 

Lonning, P.E. (2002). Aromatase inhibitors and inactivators for breast cancer treatment. Eur. J. Cancer 38(Suppl 6), S47-S48. 

Buzdar AU. Jonat W, Howell A, et al. ARIMIDEX a potent and selective aromatase inhibitor for the treatment of advanced breast cancer. J Steroid... 

Higa GM, Al-Khouri N. Anastrozole a selective aromatase inhibitor for the treatment of breast cancer. Am J Health-Syst Pharm 1998 55 445-452. 

Aromatase inhibitors are used to treat postmenopausal breast cancer. Two prime metastasis sites for breast cancer are the Inngs and bones. Negative findings in these areas indicate the medication is effective. 

Tamoxifen (Tam) (Novaldex) is an estrogen receptor antagonist present in breast tissue, with activity linked to its metabolite hydroxytamoxifen (OHTam). In other tissues (endometrium) it behaves as an agonist due to the presence of other coactivators. This SERM is involved in the endocrine therapy commonly used with hormone-dependent breast cancers, although aromatase inhibitors (Anastrozole) are also frequently used for the same female patient group. Tamoxifen is the most common hormonal treatment for breast cancer in men. It also protects against osteoporosis [17]. 

The literatnre on clinical use of aromatase inhibitors for cancer treatment is immense, and much has been published since the last version of this chapter [149], The topic has been reviewed many times [2330-2333], including some reviews by A. Brodie, a pioneer in this area [2334, 2335], Breast cancer is probably the major target area for P450 19A1 inhibition, but other cancers are also under investigation [2336],... 

While tamoxifen remains an important component of endocrine therapy for breast cancer, major clinical trials of the aroma-tase inhibitors anastrozole, letrozole, and exemestane suggest that these agents are more effective and better tolerated than tamoxifen. On the other hand, some comparative studies have suggested that the aromatase inhibitors have less favorable effects than tamoxifen on cardiovascular risk. An occasional review puts the controversy into perspective [38 ], but the debate is obscured by the publication of many papers that appear biased in favor either of tamoxifen or the inhibitors as regards efficacy, safety, or both. 

Zoledronic acid has been used to counter the adverse effects of aromatase inhibitors on bone density [SEDA-32, 753]. It seems very likely that the risk of accelerated bone loss and consequent fractures during adjuvant aromatase inhibitor therapy would similarly be reduced by the use of denosu-mab, a fully human monoclonal antibody against receptor activator of NFk-B. A US group has reported on a group of 252 patients with breast cancer and low bone mass (but no osteoporosis) taking aromatase inhibitors for long periods [42 ]. All received supplementary calcium... 

Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008 26 4875-82. 

Aromatase inhibitors (aminogluthetimide, formes-tane, trilostane) block the formation of estrogens from precursor steroids and thus lower estrogen levels. They have been used for treating breast cancer. 

In premenopausal women the ovary is the richest source of aromatase and hence estrogen. Aromatase is confined to the granulosa cells and is produced under the influence of gonadotropins (FSH and LH). Despite being a rich source of aromatase, three separate studies have shown that aromatase inhibitors are unable to sufficiently suppress ovarian estrogen production to postmenopausal levels. One explanation for this phenomenon may be a compensatory rise in gonadotrophins which maintains adequate estrogen production, despite the presence of the inhibitor. As such aromatase inhibitors cannot be used in premenopausal breast cancer patients. After menopause, ovarian... 

Aminooglutethimide was the fust aromatase inhibitor to be used in patients with metastatic breast cancer, where response rates of up to 30% have been reported. Unfortunately, due to its lack of selectivity for aromatase, it induced a medical adrenelectomy that resulted in suppression of aldosterone and cortisol. With the development of more selective aromatase... 

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. 

In postmenopausal women, recently reported evidence supporting the use of aromatase inhibitors in the adjuvant setting is intriguing and may usurp the role of tamoxifen. Three different approaches to therapy have been undertaken with these new agents (1) direct comparison with tamoxifen for adjuvant hormonal therapy, (2) sequential use after 5 years of adjuvant tamoxifen therapy, and (3) sequential use after 2 to 3 years of adjuvant tamoxifen. Based on results of several studies, it has been concluded that therapy for postmenopausal women with ER-positive breast cancer should include an aromatase inhibitor.27,47 It is still unclear if the aromatase inhibitor should be used instead of tamoxifen or sequentially after receiving tamoxifen for 2 to 5 years.27 Concerns surrounding loss of bone density, changes in blood lipids, and cardiac and vascular disease require further study.27... 

Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer Status report 2004. J Clin Oncol 2005 23 619-629. 

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